introduction to clinical hematopoietic cell transplantation …...2018/05/03 · hematopoietic cell...

Introduction to Clinical Hematopoietic Cell

Transplantation (HCT)

George Chen, MD

Thursday, May 03, 2018

Hematopoietic Cell Transplantation (HCT)

• Bone marrow transplant

• Hematopoietic stem cell transplant

• Hematopoietic progenitor cell transplant

• Peripheral blood stem cell transplant

The transfer of hematopoietic progenitor and stem cells for therapeutic purposes

Patient

Patient

Chemo ± XRT

Patient

Chemo ± XRT

Relapse

Patient

HCT

Chemo ± XRT

Relapse

Acute GvHD (15%)

Infection (10%)

Other (5%)

Chronic GvHD, dead (15%)

Disease relapse (20%)

Chronic GvHD, alive (15%)

Alive and well (20%)

Allogeneic BMT Survival Outcomes (AML)

A transplant is a bet against the future

High dose Chemo ±

XRT

Leukemia Therapy

95%

5%

55%

45%

Genetic Subgroup Analysis: RFS

time (months)

Rela

pse

-fre

e S

urv

ival (%

)

0 12 24 36 48 60 72 84 96

0

20

40

60

80

100

NPM1+/FLT3 ITD-

time (months)

Rela

pse-f

ree S

urv

ival (%

)

0 12 24 36 48 60 72 84 96

0

20

40

60

80

100

p=0.71

donor n=35

no donor n=92

donor n=45

no donor n=125

p=0.02

Others

Schlenk R et al, NEJM 2008

MUD Transplantation in Relapsed Patients

with Unfavorable Genotype

other strategy n=67

MUD n=37

p<0.0001

time (months)

Su

rviv

al

aft

er

rela

pse

(%

)

0 12 24 36 48 60

0

20

40

60

80

100

Prognostic categories for AML • Good

– t(8:21), t(9:22), inv16, t(15:17)

– NPM1

– CEPB

• Medium

– Normal karyotype

• Poor

– Multiple karyotypic abnormalities

– Flt3 ITD or TDK

• Clinical factors indicating a poor prognosis

– Induction failure, relapsed disease

– Prior hematologic disorder

– Relapsed disease

Important Concepts

• Autologous vs allogeneic HCT

• Myeloablative vs reduced intensity conditioning regimens

• Autologous, syngeneic, matched related, matched unrelated, mismatched and haploidentical donors

• Acute vs. chronic graft versus host disease

• Donor chimerism

Basic Definitions

• Autologous HCT – A transplant using a patient’s own cells for the graft.

• Allogeneic HCT – A transplant using another person’s cells for the graft.

Patient Autologous HCT

High dose Chemo ± XRT

Regular Chemo ± XRT

Freezer

8-14 days

Cyt

oto

xici

ty

Chemotherapy dose C

yto

toxi

city

Chemotherapy dose

Indications for high dose chemotherapy and autoHCT

• Chemo / radiation dose responsive malignancies

– Germ cell tumors (testicular)

– Large cell lymphoma

– Mantle cell lymphoma (usually)

– Myeloma

• Replacement of hematopoiesis (rescue therapy)

Patient

Allogeneic HCT

Regular Chemo±XRT

High dose Chemo ±

XRT

14-21 days

Time

Donor

Indications for alloHCT • Immune mediated effect against the

underlying malignancy

• Prevention of relapse

–Acute and chronic leukemia

–Myelodysplastic syndrome

–Indolent lymphomas

• Replacement of hematopoiesis

–Aplastic anemia

Autologous Allogeneic

Replace hematopoiesis

Yes Yes

Cytoreduction Yes Depends

Immune effect No * Yes

Chemotherapy dose

High High and low

21

Important Concepts





• Donor chimerism

Patient

Allogeneic BMT


High dose Chemo ±

XRT

14-21 days

Time

Donor

Cel

l Kill

ing

Chemotherapy dose Chemotherapy dose

Cel

l Kill

ing

Pat

ien

t To

xici

ty

Chemotherapy dose

Cel

l Kill

ing

Chemotherapy dose Chemotherapy dose

Cel

l Kill

ing

Pat

ien

t To

xici

ty

Chemotherapy dose

Pat

ien

t To

xici

ty

Chemotherapy dose

Patient

Allogeneic BMT


High dose Chemo ±

XRT

14-21 days

Time

Donor

Patient Non-

myeloablativeReduced Intensity AlloBMT

Regular Therapy

± Chemo ± XRT

14-21 days

Time

Donor

Immunosuppression

Nonmyeloablative

Myeloablative

Months Chemo

Chemo Months

Bo

rnh

ause

r, e

t al

. Lan

cet

On

colo

gy O

ct 2

01

2

1st CR MRD 9/10 MUD

http://www.sciencedirect.com/science/article/pii/S1470204512703492#gr2


Bo

rnh

ause

r, e

t al

. Lan

cet

On

colo

gy O

ct 2

01

2

All patients

41-60 y/o

18-40 y/o



Transplant regimens

Myelosuppression

Flu-Cy

Flu-Cy-ATG

Flu-low dose

TBI

Flu ATG

TLI/ATG

FLU/CY/TBI 200 cGy

Cy-TBI 1200 cGY

Bu-Cy

Mel 200

Flu-Mel

Flu-Bu

Flu-Mel-TBI 400 cGy

More Regimen Related Toxicity

Later Graft-versus Disease Effect Earlier Anti-Disease Effect

Allo Non- myeloablative

Allo Reduced Intensity

Auto and Allo Myeloablative

More Relapse

Bu, Mel, full dose TBI (~12 Gy)

Fludarabine Bu, Mel, full dose TBI

Cyclophosphamide

Fludarabine Bu, Mel, full dose TBI

Cyclophosphamide

4-hydroxy-cyclophosphamide

Cytochrome P450

Aldophosphamide

Phosphoramide mustard (active)

Acrolein (active)

Aldehyde dehydrogenase Carboxy

phosphamide (inactive)

Tautomer-ization

Cyclophosphamide


Cytochrome P450

Aldophosphamide


Acrolein (active)



Tautomer-ization

Elevated in stem cells Higher in resting lymphocytes versus activated lymphocytes

Auto Allo RIC Allo MA

Replace hematopoiesis

Yes Yes Yes

Cytoreduction Yes Some Theoretically more

Immune effect No * Yes Yes

Chemotherapy dose

High Less More

Patient toxicity Yes Less More

38

Important Concepts





• Donor chimerism

Human Leukocyte Antigen (HLA) • Proteins which present antigenic peptides to

T cells

• On surface of most body cells

• The most important proteins in transplant

• Responsible for graft rejection and GvHD

HLA

• Class I – A, B, C

• Class II – DR, DQ, DP

HLA

• (>1 * 1012 haplotypes)2 = > 1 * 1024 combinations

• Frequencies are not equal distributed

• Not all alleles have been identified

HLA DRB1 A B C DQB1

Alleles 400 370 660 190 62

HLA Inheritance

Chance of a matched sibling = 1 – 0.75 # of other siblings

Haplotype – the set of HLA genes inherited from one parent

A2 B7

DR01

A23 B51

DR04

A11 B15

DR11

A30 B35

DR13

A2 B7

DR01

A11 B15

DR11

A23 B51

DR04

A11 B15

DR11

A2 B7

DR01

A30 B35

DR13

A23 B51

DR04

A30 B35

DR13

Matched Donor 6/6 HLA Matched

Maternal haplotype

Paternal haplotype

DRB1 DRB1

B B

A A

C C

DQ DQ

DP DP

Maternal haplotype

Paternal haplotype

DRB1 DRB1

B B

A A

C C

DQ DQ

DP DP

Donor Recipient

Matched Donor 8/8 HLA Matched

Maternal haplotype

Paternal haplotype

DRB1 DRB1

B B

A A

C C

DQ DQ

DP DP

Maternal haplotype

Paternal haplotype

DRB1 DRB1

B B

A A

C C

DQ DQ

DP DP

Donor Recipient

Matched Donor 10/10 matched

Maternal haplotype

Paternal haplotype

DRB1 DRB1

B B

A A

C C

DQ DQ

DP DP

Maternal haplotype

Paternal haplotype

DRB1 DRB1

B B

A A

C C

DQ DQ

DP DP

Donor Recipient

Matched UnRelated Donor 10/10 HLA matched DP matched

12/12 HLA Matched

Maternal haplotype

Paternal haplotype

DRB1 DRB1

B B

A A

C C

DQ DQ

DP DP

Maternal haplotype

Paternal haplotype

DRB1 DRB1

B B

A A

C C

DQ DQ

DP DP

Donor Recipient

Haploidentical Donor 3/6 HLA matched

Anything ≤4/6 HLA matched

Maternal haplotype

Paternal haplotype

DRB1 DRB1

B B

A A

C C

DQ DQ

DP DP

Maternal haplotype

Paternal haplotype

DRB1 DRB1

B B

A A

C C

DQ DQ

DP DP

Donor Recipient

Maternal haplotype

Paternal haplotype

DRB1-1 DRB1-2

B-1 B-2

A-1 A-2

C-1 C-2

DQ-1 DQ-2

DP-1 DP-2

Maternal haplotype

Paternal haplotype

DRB1-1 DRB1-2

B-1 B-2

A-3 A-2

C-1 C-2

DQ-1 DQ-2

DP-1 DP-2

A antigen mismatched donor

Donor Recipient

Maternal haplotype

Paternal haplotype

DRB1 DRB1

B B

A A

C C

DQ DQ

DP DP

Maternal haplotype

Paternal haplotype

DRB1 DRB1

B B

A A

C C

DQ DQ

DP DP

Maternal haplotype

Paternal haplotype

DRB1 DRB1

B B

A A

C C

DQ DQ

DP DP

Pidala, et al. Blood 2015

Recipient Donor Donor

HLA Expression Level

• High expression level (HEL) antigens – DRB1, A, B, C

• Low expression level (LEL) antigens – DQ, DP, DRB3-5

MisMatched UnRelated Donor High vs Low Expression Level Antigens

Maternal haplotype

Paternal haplotype

DRB1 DRB1

B B

A A

C C

DQ DQ

DP DP

Maternal haplotype

Paternal haplotype

DRB1 DRB1

B B

A A

C C

DQ DQ

DP DP

Maternal haplotype

Paternal haplotype

DRB1 DRB1

B B

A A

C C

DQ DQ

DP DP

Pidala, et al. Blood 2015

Recipient Donor Donor

Relative degree of mismatch

Maternal haplotype

Paternal haplotype

DRB1 DRB1

B B

A A

C C

DQ DQ

DP DP

Maternal haplotype

Paternal haplotype

DRB1 DRB1

B B

A A

C C

DQ DQ

DP DP

Maternal haplotype

Paternal haplotype

DRB1 DRB1

B B

A A

C C

DQ DQ

DP DP

Recipient Donor Donor Maternal haplotype

Paternal haplotype

DRB1 DRB1

B B

A A

C C

DQ DQ

DP DP

Donor

Donor Selection

• Human leukocyte antigen (HLA) matching

• Relatedness

• Cytomegalovirus status

• Age

• Gender (parity)

• Not blood ABO type

Important Concepts





• Donor chimerism

Immunologic Effects of Allogeneic Grafts

• Graft-versus-Tumor Effects – Reaction of the donor immune system against the recipient’s malignancy

• Graft-versus-Host Effects – Reaction of the donor immune system against the recipient’s body tissues.

• Different sides of the same coin.

Probability of Relapse After 2,254 HLA-identical Sibling Transplants for

Early Leukemia

Mln06_1.ppt

0 2 4 6 1 3 5

0

20

40

60

80

100

Pro

bab

ility

of

Re

lap

se, %

Years

T Cell Depletion (n=401)

Twins (N=70)

No GVHD (n=433)

AGVHD Only (n=738)

AGVHD + CGVHD (N=485)

CGVHD Only (N=127)

Incr

eas

ing

GV

T

Incr

eas

ing

GV

H

Acute GvHD 100 Day Survival

Grade I 78-90%

Grade II 66-92%

Grade III 29-62%

Grade IV 23-25%

Prevention/Control of aGvHD Is Important

(Przepiorka et al, 1995)

Acute GvHD

• Reaction of donor’s immune system against the recipient’s body tissues

• Manifests as diarrhea, skin rash, liver test abnormalities usually within the first 100 days.

• ~20-50% of allogeneic transplants will develop some aGvHD

• Associated with a 15-20% mortality

• Prophylaxis – Prevention of aGvHD

• Treatment – Therapy of aGvHD

Patient

Allogeneic BMT


High dose Chemo ±

XRT

14-21 days

Time

Donor

Acute GvHD Prophylaxis

• Micro methotrexate

• Post transplant cyclophosphamide

• Alpha beta T cell depletion and CD34 selection

Billingham Criteria (1966) • The graft must contain immunologically

competent cells

• The host must possess important transplantation alloantigens that are lacking in the donor graft, so that the host appears foreign to the graft, and is, therefore, capable of stimulating it antigenically

• The host itself must be incapable of mounting an effective immunological reaction against the graft, at least for sufficient time for the latter to manifest its immunological capabilities; that is, it (the graft) must have the security of tenure

Cyclophosphamide


Cytochrome P450

Aldophosphamide


Acrolein (active)



Tautomer-ization

Elevated in stem cells Higher in resting lymphocytes versus activated lymphocytes

MMF and tacrolimus

High dose CY

Graft

-6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 Day

TAC and MMF

FLU-CY-TBI

MMF and tacrolimus

High dose CY

Graft

-6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 Day

TAC and MMF

FLU-CY-TBI

T cell proliferation

MMF and tacrolimus

High dose CY

Graft

-6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 Day

TAC and MMF

CY

FLU-CY-TBI

T cell proliferation

Post HCT cyclophosphamide (Cy) for GvHD

Day 0

73


74


75


Cy Cy

76


Cy Cy

X X 77


78


79

Acute GvHD Prophylaxis

• Micro methotrexate

• Post transplant cyclophosphamide

• Alpha beta T cell depletion and CD34 selection

Billingham Criteria (1966) • The graft must contain immunologically

competent cells

• The host must possess important transplantation alloantigens that are lacking in the donor graft, so that the host appears foreign to the graft, and is, therefore, capable of stimulating it antigenically

• The host itself must be incapable of mounting an effective immunological reaction against the graft, at least for sufficient time for the latter to manifest its immunological capabilities; that is, it (the graft) must have the security of tenure

αβ T Cell Depletion


83


84


85

Patient


86


87

WASTE

CD34+ Cell Selection

88


WASTE


Patient

RPCI Prophylaxis Regimens Ab-TCD Pt-Cy uMTX

Active agent

Clinimacs Cyclophos-phamide

Metho-trexate

Target Alpha beta T cells

Proliferating T cells

Proliferating T cells

Place of action

Ex vivo In vivo In vivo

T cell Depletion Depletion Inhibition

Other Tacro Tacro Cellcept

Tacro Cellcept

94

Probability of Relapse After 2,254 HLA-identical Sibling Transplants for

Early Leukemia

Mln06_1.ppt

0 2 4 6 1 3 5

0

20

40

60

80

100

Pro

bab

ility

of

Re

lap

se, %

Years

T Cell Depletion (n=401)

Twins (N=70)

No GVHD (n=433)

AGVHD Only (n=738)

AGVHD + CGVHD (N=485)

CGVHD Only (N=127)

Incr

eas

ing

GV

T

Incr

eas

ing

GV

H

Chronic Graft-versus-Host Disease • Post transplant complication usually

occurring > 100 days characterized by

– Fibrotic skin disease

– Dry and gritty mouth eyes due to glandular destruction

– Gastrointestinal fibrosis with malnutrition

• 50% of long term survivors will develop some form of cGvHD

• Chronic GvHD is the major cause of long term mortality other than relapse after transplant

C

B

C

D

D

introduction to clinical hematopoietic cell transplantation …...2018/05/03 · hematopoietic cell...

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